System for providing fluid flow to nerve tissues

ABSTRACT

Provided is an apparatus that includes a nerve conduit, a manifold and a support structure for providing a reduced pressure. Also provided is a system that includes a source of reduced pressure, a nerve conduit, a manifold, a support structure and a conduit for providing fluid communication between the manifold support and the source of reduced pressure. Additionally provided is a method that includes implanting the above nerve conduit, manifold and support structure at a site of damaged nerve tissue and applying a reduced pressure to the manifold thereby stimulating repair or regrowth of nerve tissue.

This application claims priority to U.S. Provisional Application Nos.61/142,053 and 61/142,065, each filed on Dec. 31, 2008. This applicationalso claims priority to U.S. Provisional Application No. 61/234,692,filed on Aug. 18, 2009 and U.S. Provisional Application No. 61/238,770,filed on Sep. 1, 2009. Each of the foregoing applications isincorporated herein by reference in their entirety.

BACKGROUND

1. Field of the Invention

The present application relates generally to tissue engineering and inparticular to apparatuses and systems suitable for use in treatment ofdamaged nerve tissue.

2. Description of Related Art

Clinical studies and practice have shown that providing a reducedpressure in proximity to a tissue site augments and accelerates thegrowth of new tissue at the tissue site. The applications of thisphenomenon are numerous, but application of reduced pressure has beenparticularly successful in treating wounds. This treatment (frequentlyreferred to in the medical community as “negative pressure woundtherapy,” “reduced pressure therapy,” or “vacuum therapy”) provides anumber of benefits, including faster healing and increased formation ofgranulation tissue. Typically, reduced pressure has been applied totissue through a porous pad or other manifolding device. The porous padcontains pores that are capable of distributing reduced pressure to thetissue and channeling fluids that are drawn from the tissue. The porouspad often is incorporated into a dressing having other components thatfacilitate treatment. A scaffold can also be placed into a defect tosupport tissue growth into the defect. The scaffold is usuallybioabsorbable, leaving new tissue in its place.

Scaffolds for reduced pressure treatment are described in, e.g.,WO08/091,521, WO07/092,397, WO07/196,590, WO07/106,594. The adequacy ofcurrent scaffolds for reduced pressure treatment can be evaluated inlight of current knowledge of wound healing. Injury to body tissuesresults in a wound healing response with sequential stages of healingthat include hemostasis (seconds to hours), inflammation (hours todays), repair (days to weeks), and remodeling (weeks to months). A highlevel of homology exists across most tissue types with regards to theearly phases of the wound healing process. However, the stages ofhealing for various tissues begin to diverge as time passes, with theinvolvement of different types of growth factors, cytokines, and cells.The later stages of the wound healing response are dependent upon theprevious stages, with increasing complexity in the temporal patterningof and interrelationships between each component of the response.

Strategies to facilitate normal repair, regeneration, and restoration offunction for damaged tissues have focused on methods to support andaugment particular steps within this healing response, especially thelatter aspects of it. To this end, growth factors, cytokines,extracellular matrix (ECM) analogs, exogenous cells and variousscaffolding technologies have been applied alone or in combination withone another. Although some level of success has been achieved using thisapproach, several key challenges remain. One main challenge is that thetiming and coordinated influence of each cytokine and growth factorwithin the wound healing response complicate the ability to addindividual exogenous factors at the proper time and in the correctcoordination pattern. The introduction of exogenous cells also facesadditional complications due to their potential immunogenicity as wellas difficulties in maintaining cell viability.

Synthetic and biologic scaffolds have been utilized to providethree-dimensional frameworks for augmenting endogenous cell attachment,migration, and colonization. To date nearly all scaffolds have beendesigned with the idea that they can be made to work with the biology.Traditional scaffolding technologies, however, rely on the passiveinflux of endogenous proteins, cytokines, growth factors, and cells intothe interstitium of the porous scaffold. As such, the colonization ofendogenous cells into the scaffold is limited by the distance away fromvascular elements, which provide nutrient support within a diffusionlimit of the scaffold, regardless of tissue type. In addition, thescaffolds can also elicit an immunogenic or foreign body response thatleads to an elongated repair process and formation of a fibrous capsulearound the implant. Taken together, these complications can all lead toless than functional tissue regeneration at the injury site.

It would therefore be advantageous to provide additional systems for therepair and remodeling of specialized tissues. The present inventionprovides such systems.

SUMMARY

The apparatuses, systems and methods of the illustrative embodimentsdescribed herein provide active guidance of nerve tissue repair andregeneration through an implanted manifold and nerve conduit. In oneembodiment, an apparatus for providing reduced pressure therapy andfacilitating growth of nerve tissue in a patient is provided thatincludes a nerve conduit, a manifold and manifold support structureadaptable for implantation at a damaged nerve site, wherein the manifoldprovides and distributes a reduced pressure at the site of damaged nervetissue. A manifold according to the invention may also serve as or becoupled to a scaffold which further distributes reduced pressure andprovides a structural matrix for growth of the tissue.

In certain embodiments an apparatus according to the invention comprisesa nerve conduit, a manifold and at least a first support structure. Anerve conduit, in certain aspects, comprises a generally tubular shapehaving walls including an exterior wall and a luminal wall surroundingthe tissue site to contain fluids within a luminal space between thetissue site and the luminal wall. In some instances, a manifoldaccording to the invention comprises a generally cylindrical body havingsurfaces including a side wall surface and two end wall surfaces, afirst end wall surface of the two end wall surfaces for receivingreduced pressure, a fluid contact surface including a first portion ofthe surfaces of the cylindrical body other than the first end wallsurface for fluid communication with the luminal space, and a supportsurface including a second portion of the surface of the cylindricalbody other than the first end wall surface and the fluid contactsurface. A support structure according to the invention may comprise agenerally tubular shape for enclosing the support surface, a first endportion for coupling the first end wall surface to the reduced-pressuresource, and a second end portion for coupling the manifold to the nerveconduit in a generally radial direction with respect to the luminalwall.

In another embodiment, a system for providing reduced pressure therapyand facilitating growth of nerve tissue in a patient is provided thatcomprises a source of reduced pressure for supplying reduced pressureand an apparatus including a nerve conduit, manifold and supportstructure adaptable for implantation at the tissue site, where themanifold is in fluid communication with the source of reduced pressure.In a further embodiment, such a system may further comprise a canisterfor fluid capture and/or a valve for control of reduced pressure influid communication with, and positioned between, the manifold and thereduced pressure source. In still a further embodiment, a systemaccording to the invention further comprises a fluid source in fluidcommunication with the manifold and the damaged nerve tissue.

In still a further embodiment, a method of providing reduced pressuretherapy and facilitating growth of nerve tissue at site of nerve tissuedamage in a patient is provided that includes implanting a nerveconduit, manifold and support structure at the tissue site, where themanifold provides a reduced pressure to the damaged nerve tissue. Themanifold may also serve as or be coupled to a scaffold material, whereinthe scaffold material provides a structural matrix for the growth of thenerve tissue. In certain embodiments, the method further comprisesproviding a manifold in fluid communication with a fluid source, whereinthe fluid source may be used to deliver a fluid to the manifold and thedamaged nerve tissue. In yet a further embodiment, the fluid source maycomprise a fluid comprising one or more bioactive compounds including,but not limited to, an antibiotic, an antiviral, a cytokine, achemokine, an antibody and a growth factor.

Other objects, features, and advantages of the illustrative embodimentswill become apparent with reference to the drawings and detaileddescription that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-B is a schematic, perspective view of a reduced pressuretreatment system for repairing a severed (FIG. 1A) or a pinched nerve(FIG. 1B) including a nerve conduit and a first embodiment of a manifoldwith a section of the nerve conduit removed to show the manifold;

FIG. 2 is a schematic of a reduced pressure treatment system forrepairing a severed or partially severed nerve including a nerve conduitand a second embodiment of a manifold with a section of the nerveconduit removed to show the manifold;

FIG. 3 is a schematic of a reduced pressure treatment system forrepairing a severed or partially severed nerve including a nerve conduitand a third embodiment of a manifold with a section of the nerve conduitremoved to show the manifold; and

FIG. 4 is a schematic, perspective view of the system shown in FIGS. 1-3showing the nerve conduit enclosing the damaged nerve; and

FIG. 5 is a schematic view of a fluid control system for the systemshown in FIGS. 1-3.

DETAILED DESCRIPTION

In the following detailed description of the illustrative embodiments,reference is made to the accompanying drawings that form a part hereof.These embodiments are described in sufficient detail to enable thoseskilled in the art to practice the invention, and it is understood thatother embodiments may be utilized and that logical structural,mechanical, electrical, and chemical changes may be made withoutdeparting from the spirit or scope of the invention. To avoid detail notnecessary to enable those skilled in the art to practice the embodimentsdescribed herein, the description may omit certain information known tothose skilled in the art. The following detailed description is,therefore, not to be taken in a limiting sense, and the scope of theillustrative embodiments are defined only by the appended claims.

Referring to FIG. 1A-B, a reduced pressure therapy system 100 forapplying reduced pressure at a tissue site in the body of a patient torepair a defect such as, for example, a damaged nerve is disclosed. Thedamaged nerve may have been pinched, partially disconnected or severed,or partially degenerated as a result of disease. For example, thedamaged nerve in FIG. 1A is a severed nerve 102 having a proximalsegment 104 and a distal segment 106 relative to the central nervoussystem (CNS) of the patient. FIG. 1B illustrates a reduced pressuretherapy system and this case the damaged nerve is a pinched nerve 103that has been damaged at a nerve damage site 108. In this case, thenerve has been pinched, partially severed or partially degenerated, buthas not been completely severed. The nerve may be branched or unbranchedat the nerve damage site 108. The term “nerve damage site” as usedherein refers to a wound or defect located on or within any nervetissue, including, but not limited to, a disconnected or partiallydisconnected nerve, a degenerated or partially degenerated nerve, and acompressed or pinched nerve. For example, reduced pressure tissuetreatment may be used to enhance repair or regrowth of existing nervetissue or to facilitate growth or grafted or transplanted nerve tissueand/or cells.

The reduced pressure therapy system 100 comprises a nerve conduit 110that surrounds the pinched nerve 103 at the nerve damage site 108 with asection of the nerve conduit 110 removed to show the nerve damage site108. The nerve conduit 110 is substantially tubular in shape and closesthe nerve damage site 108 and a portion of the proximal segment 104 andthe distal segment 106 that has not been damaged. The nerve conduit 110has an exterior surface 113 and an inner surface 112 that forms a nervegap 114 with the surface of the nerve damage site 108, i.e., a luminalspace between the inner surface 112 of the nerve conduit 110 and thesurface of the nerve damage site 108. The reduced pressure therapysystem 100 also comprises a reduced pressure source 115 for providing areduced pressure and a manifold 120 fluidly coupled to the pressuresource 115 via a first conduit 125. The manifold 120 is contained withina manifold chamber 121 having a flange 122 extending from one end of themanifold chamber 121 for securing the manifold chamber 121 to the nerveconduit 110. The other end of the manifold chamber 121 is connected tothe first conduit 125 so that the manifold 120 is held in fluidcommunication with the first conduit 125. The manifold chamber 121 maybe constructed of any biocompatible material that is substantiallyimpermeable to preserve the manifold's 120 fluid communication betweenthe nerve gap 114 and the first conduit 125. The manifold chamber 121 issecured to the nerve conduit 110 by the flange 122 such that themanifold 120 is in fluid communication with the nerve gap 114surrounding the surface of the nerve damage site 108, but positionedoutside of the nerve gap 114. In certain aspects, the flange 122 issecured to the nerve conduit 110 with an adhesive. Moreover, in someapplications, the flange 122 is detachably secured to the nerve conduit110 such that the flange 122 and manifold chamber 121 can be removedfrom the nerve conduit 110 after reduced pressure therapy is complete.In one embodiment, the manifold 120 extends through the wall of thenerve conduit 110 in direct fluid contact with the nerve gap 114. Inanother embodiment, where the nerve conduit 110 is porous, the flange122 is secured to the exterior surface 113 of the nerve conduit 110 sothat the manifold 120 is positioned adjacent to the exterior surface 113to be in fluid communication with the nerve gap 114 via the porous wallof the nerve conduit 110.

The manifold 120 may have a variety of shapes depending on the type ofnerve damage, and depending on how the manifold is positioned in fluidcontact with the nerve gap 114 around the nerve damage site 108. Themanifold may also be coupled with a flange 122 that is in turn coupledto the exterior surface of the nerve conduit 113. The flange 122 forms aseal between the exterior surface of the nerve conduit 113 and themanifold 120 to prevent reduced pressure from being applied outside ofthe nerve conduit 110. The lumen of the nerve conduit and the nerve gap114 may also contain a scaffold material (not shown) that provides astructure for tissue growth and repair. The reduced pressure therapysystem 100 further comprises a canister 130 fluidly coupled between thereduced pressure source 115 and the manifold 120 via the conduit 125 tocollect bodily fluids such as blood or exudate that are drawn from thenerve gap 114. In one embodiment, the reduced pressure source 115 andthe canister 130 are integrated into a single housing structure.

As used herein, the term “coupled” includes direct coupling or indirectcoupling via a separate object. The term “coupled” also encompasses twoor more components that are continuous with one another by virtue ofeach of the components formed from the same piece of material. Also, theterm “coupled” may include chemical, mechanical, thermal, or electricalcoupling. Fluid coupling means that fluid is in communication withdesignated parts or locations.

In the context of this specification, the term “reduced pressure”generally refers to a pressure that is less than the ambient pressure ata tissue site that is subjected to treatment. In most cases, thisreduced pressure will be less than the atmospheric pressure of thelocation at which the patient is located. Although the terms “vacuum”and “negative pressure” may be used to describe the pressure applied tothe tissue site, the actual pressure applied to the tissue site may besignificantly greater than the pressure normally associated with acomplete vacuum. Consistent with this nomenclature, an increase inreduced pressure or vacuum pressure refers to a relative reduction ofabsolute pressure, while a decrease in reduced pressure or vacuumpressure refers to a relative increase of absolute pressure. The term“−Δp” means change in reduced pressure. As used herein, a greater (i.e.,more negative) −Δp means increased negative pressure (i.e., a greaterchange in pressure from ambient pressure). Reduced pressure treatmenttypically applies reduced pressure at −5 mm Hg to −500 mm Hg, moreusually −5 to −300 mm Hg, including but not limited to −50, −125 or −175mm Hg. Reduced pressure may be constant at a particular pressure levelor may be varied over time. For example, reduced pressure may be appliedand stopped periodically or ramped-up or -down over time.

As indicated above, a nerve damage site may be a wound or defect locatedon or within any nerve tissue including, for example, a completelysevered nerve 102 having a proximal segment 104 and a distal segment 106relative to the CNS of the patient as shown in FIG. 2. The severed nerve102 has been damaged at a nerve damage site 108 that has been completelysevered. Another reduced pressure therapy system 200 for applyingreduced pressure at the nerve damaged site 108 comprises similarcomponents as the reduced pressure therapy system 100 as indicated bythe same reference numerals. The reduced pressure therapy 200 comprisesthe nerve conduit 110 that surrounds the nerve damage site 108 and thesevered ends of the severed nerve 102. The inner surface 112 of thenerve conduit 110 forms a nerve gap 114 between the severed ends of thesevered nerve 102 within the nerve damage site 108, i.e., a luminalspace between the inner surface 112 of the nerve conduit 110 and thesurface of the nerve damage site 108. The reduced pressure therapysystem 200 also comprises a manifold 220 fluidly coupled to the pressuresource 115 via the first conduit 125 and to the nerve gap 114. Themanifold 220 is also partially contained with-in a manifold chamber 221having a flange 222 for securing the manifold chamber 221 to the nerveconduit 110 and otherwise the same as the manifold chamber 121. Unlikethe manifold 120, the manifold 220 comprises a manifold protrusion 225that extends into the nerve gap 114. The manifold 220 and manifoldprotrusion 225 may have a variety of shapes depending on the type ofnerve damage, and depending on how the manifold is positioned in fluidcontact with the nerve gap 114 around the nerve damage site 108. Theflange 222 forms a seal between the exterior surface of the nerveconduit 113 and the manifold chamber 221 to prevent reduced pressurefrom being applied outside of the nerve conduit 110. In certain aspects,the flange 222 is secured to the nerve conduit 110 with an adhesive.Moreover, in some applications, the flange 222 is detachably secured tothe nerve conduit 110 such that the flange 222 and manifold chamber 221can be removed from the nerve conduit 110 after reduced pressure therapyis complete. The manifold protrusion 225 may be formed of a material sothat the manifold protrusion also functions as a scaffold that providesa structure for tissue growth and repair. The reduced pressure therapysystem 200 further comprises a canister 130 fluidly coupled between thereduced pressure source 115 and the manifold 220 via the conduit 125 tocollect bodily fluids such as blood or exudate that are drawn from thenerve gap 114. In one embodiment, the reduced pressure source 115 andthe canister 130 are integrated into a single housing structure.

Still another reduced pressure therapy system 300 for applying reducedpressure at the nerve damaged site 108 is illustrated in FIG. 3. Acompletely severed nerve 102 is shown having a proximal segment 104 anda distal segment 106 relative to the CNS. The severed nerve 102 has beendamaged at a nerve damage site 108 that has been completely severed. Thereduced pressure therapy 300 comprises the nerve conduit 110 thatsurrounds the nerve damage site 108 and the severed ends of the severednerve 102. The inner surface 112 of the nerve conduit 110 forms a nervegap 114 between the severed ends of the severed nerve 102 within thenerve damage site 108, i.e., a luminal space between the inner surface112 of the nerve conduit 110 and the surface of the nerve damage site108. The reduced pressure therapy system 300 also comprises a manifold320 fluidly coupled to the pressure source 115 via the first conduit 125and to the nerve gap 114. The manifold 320 is also partially containedwith-in manifold chambers 321 each having a flange 322 for securing themanifold chambers 321 to the nerve conduit 110 and otherwise the same asthe manifold chamber 121 and 221. Unlike the manifold 220, the manifold320 extends into and through the nerve gap 114 and is secured on bothsides of the nerve conduit 110 by a manifold chamber 321 and flange 322.The manifold 320 may have a variety of shapes depending on the type ofnerve damage, and depending on how the manifold is positioned in fluidcontact with the nerve gap 114 around the nerve damage site 108. Theflanges 322 form a seal between the exterior surface of the nerveconduit 113 and the manifold chambers 321 to prevent reduced pressurefrom being applied outside of the nerve conduit 110. In certain aspects,the flanges 322 are secured to the nerve conduit 110 with adhesive. Insome applications, one or both flanges 322 are detachably secured to thenerve conduit 110 such that the flange(s) 322 and manifold chamber(s)321 can be removed from the nerve conduit 110 after reduced pressuretherapy is complete. The manifold 320 may be formed of material so thatthe manifold also functions as a scaffold that provides a structure fortissue growth and repair. The reduced pressure therapy system 300further comprises a canister 130 fluidly coupled between the reducedpressure source 115 and the manifold 320 via the conduit 125 to collectbodily fluids such as blood or exudate that are drawn from the nerve gap114. In one embodiment, the reduced pressure source 115 and the canister130 are integrated into a single housing structure. The reduced pressuretherapy system 300 further comprises a fluid source 150 in fluidcommunication with the manifold 320 via a second conduit 325.Accordingly, in a certain aspect fluid flows from the fluid source 150into the manifold 320 and the nerve gap 114 and ultimately is capturedby the canister 130. Fluid flow through the manifold transversing thesite of nerve damage 108 may help to prevent clogging of the manifold.

As indicated above, the nerve conduit 110 is shown in FIGS. 1-3 with asection removed, but shown as completely surrounding the nerve damagesites 108 as a closed nerve conduit 410 in FIG. 4. After the manifolds120, 220, 320 are inserted in the nerve gap 114 or attached to the nerveconduit 110 adjacent to the nerve gap 114, the nerve conduit 110 may besealed by utilizing one or more stitches 415 or any other fasteningdevice known in the art. The nerve conduit 110 may be composed of abioabsorbable or a bioinert material. Materials that may be used fornerve conduits include, without limitation, polylactic acid (PLA),polyglycolic acid (PGA), polylactide-co-glycolide (PLGA),polyvinylpyrrolidone, polycaprolactone, polycarbonates, polyfumarates,caprolactones, polyamides, polysaccharides (including alginates (e.g.,calcium alginate) and chitosan), hyaluronic acid, polyhydroxybutyrate,polyhydroxyvalerate, polydioxanone, polyorthoesthers, polyethyleneglycols, poloxamers, polyphosphazenes, polyanhydrides, polyamino acids,polyacetals, polycyanoacrylates, polyurethanes, polyacrylates,ethylene-vinyl acetate polymers and other acyl substituted celluloseacetates and derivatives thereof, polystyrenes, polyvinyl chloride,polyvinyl fluoride, poly(vinylimidazole), chlorosulphonated polyolefins,polyethylene oxide, polyvinyl alcohol, Teflon®, and nylon. In certainaspects, biological (e.g., purified or recombinant) materials may beused form nerve conduits including, but not limited to, fibrin,fibronectin or collagen (e.g., DURAMATRIX™).

A nerve conduit 110 may be an unbroken substantially tubular structurefitted across a gap between a proximal and distal nerve stump such asdepicted in FIG. 3. Examples of such substantially tubular nerveconduits, also referred to as nerve guides, include without limitationNEURAGEN® and NEUROFLEX™ collagen conduits. A nerve conduit may also beformed from a wrap that is positioned around a disconnected or damaged(e.g., pinched) nerve and sealed with a closure, such as a suture.Specific examples of wrap-type nerve conduits include, withoutlimitation, NEUROMEND™ and NEURAWRAP™ collagen conduits. In certainaspects, the nerve conduit is made of a material that encloses thedamaged nerve, so as to exclude infiltration of non-nerve cells, such asglia. In some embodiments, the nerve conduit material is permeable,thereby allowing fluid and protein factors to diffuse through theconduit. For example, the pores in a nerve conduit may be sufficientlysmall so as to exclude the entry of cells into the conduit lumen (e.g.,pores having an interior diameter or average interior diameter ofbetween about 5 μm and 50 μm, 10 μm and 30 μm or 10 μm and 20 μm). Thus,when reduced pressure is applied to the interior of the conduit fluidand proteins may be drawn to the lumen of the conduit by the pressuregradient. The skilled artisan will recognize that the dimensions of theconduit may be adjusted for any particular nerve application. Generally,the conduits comprise an internal diameter of less than about 6.0 mm,such as about 5, 4, 3, 2.5 or 2 mm.

Referring to FIG. 5, the reduced pressure therapy system 100, 200 or 300may further comprise a pressure sensor 140 operably connected to thefirst conduit 125 to measure the reduced pressure being applied to themanifolds 120, 220, 320. The system further includes a control unit 145electrically connected to the pressure sensor 140 and the reducedpressure source 115. The pressure sensor 140 measures the reducedpressure within the nerve gap 114, and also may indicate whether thefirst conduit 125 is occluded with blood or other bodily fluids. Thepressure sensor 140 also provides feedback to control unit 145 whichregulates the reduced pressure therapy being applied by the reducedpressure source 115 through the first conduit 125 to the manifolds 120,220, 320.

The reduced pressure therapy system 100, 200 or 300 may also comprise afluid supply 150 fluidly coupled to the first conduit 125 via a secondconduit 152 and operatively connected to the control unit 145. The fluidsupply 150 may be used to deliver growth and/or healing agents to thenerve damage site 108 including, without limitation, an antibacterialagent, an antiviral agent, antibody, a cell-growth promotion agent, anirrigation fluid, or other chemically active agents. The system 100,200, 300 further comprises a first valve 154 positioned in the secondconduit 152 to control the flow of fluid therethrough, and a secondvalve 156 positioned in the first conduit 125 between the reducedpressure supply 115 and the juncture between the first conduit 125 andthe second conduit 152 to control the flow of reduced pressure. In thecase of a reduced pressure therapy system 300, the fluid supply 150 isdirectly coupled to the manifold 320 at the nerve tissue damage site 108via the second conduit 325 as represented by the dashed lines. Thecontrol unit 145 is operatively connected to the first and second valves154, 156 to control the delivery of reduced pressure and/or fluid fromthe fluid supply 150, respectively, to the manifolds 120, 220, 320 asrequired by the particular therapy being administered to the patient.The fluid supply 150 may deliver the liquids as indicated above, but mayalso deliver air to the manifolds 120, 220, 320 to promote healing andfacilitate drainage at the site of the nerve damage site 108.

As used herein, the term “manifold” refers to a substance or structurethat is provided to assist in directing reduced pressure to, deliveringfluids to, or removing fluids from a tissue site. A manifold can includea plurality of flow channels or pathways that are interconnected toimprove distribution of fluids provided to and removed from the area oftissue around the manifold. Examples of manifolds may include withoutlimitation devices that have structural elements arranged to form flowchannels, cellular foams such as open-cell foam, porous tissuecollections, and liquids, gels and foams that include or cure to includeflow channels. A detailed description of manifolds and their useaccording to the invention is provided below. In embodiments wherein themanifold protrudes into the nerve gap 114 or extends through the nervegap 114 manifold materials that are bioabsorbable may be employed asdetailed below.

The term “scaffold” as used herein refers to a substance or structureapplied to or in a wound or defect that provides a structural matrix forthe growth of cells and/or the formation of tissue. A scaffold is oftena three dimensional porous structure. The scaffold can be infused with,coated with, or comprised of cells, growth factors, extracellular matrixcomponents, nutrients, integrins, or other substances to promote cellgrowth. A scaffold can take on characteristics of a manifold bydirecting flow through the matrix. A manifold can transmit flow to thescaffold and tissue; in the context of reduced pressure treatment, themanifold can be in fluid communication with the scaffold. A detaileddescription of scaffolds and their use according to the invention isprovided below.

As such, the invention disclosed here discloses methods and apparatusesfor controlling cellular-level based patterns of fluid flow that allowfor control of patterned protein organization at a microscopic,nanoscopic, or mesoscopic scale amenable to provide a structuredmanifold and, optionally, a scaffold material for cellular migration,differentiation, and like behavior necessary for functional regenerationof tissues. In comparison to the passive nature of the current state ofthe art with regards to tissue repair and regeneration, the methods,scaffolds, manifolds, flow sources and systems disclosed herein providean active mechanism by which to promote the endogenous deposition ofproteins and organization of the provisional matrix with biochemical andphysical cues to direct cellular colonization of a scaffold or tissuespace. The present invention thus enhances current technology byexploiting the active force of directed fluid flow, providing aframework upon which to design manifolds and scaffolds based upon theneed of the biology under the influence of fluid flow. Flow vectors andpathways are utilized to enhance protein deposition and cellularcolonization. The systems provided herein are designed to promoteestablishment of a provisional matrix network with a seamless transitionfrom the healthy tissue edges through a scaffold or tissue site topromote a functional tissue continuum.

Thus, the apparatuses, methods and systems disclosed herein provide ameans for active guidance of tissue regeneration through an implantedscaffold or within a tissue site to promote functional recovery. Thisactive guidance occurs through mechanisms of controlled fluid flow,which can be used to initiate or augment the early stages of the body'sown natural healing process; a manifold can provide the active guidancenecessary to create a controlled fluid flow. Specifically, thecontrolled flow vectors that the manifolds provide can be used tofacilitate the directed influx of cells and proteins into a scaffold.Creation of specific flow pathways within a tissue site or scaffold canlead to patterned deposition of proteins, such as collagen and fibrinwithin the manifold, scaffold or tissue space. Biochemical cues fromcytokines, growth factors, and cells bound within the provisional matrixcan work in conjunction with the natural physical cues of theprovisional matrix and extracellular matrix to guide the subsequentmigration of endogenous cells during the repair stages of healing. Thesecues act as a form of track or gradient that emanates from surroundinghealthy tissues and passes through the scaffolding or tissue space tofacilitate a continuous guidance pathway for organized tissueregeneration.

To that end, this disclosure provides unique manifolding technologiesdesigned for specific biological needs based upon principles of fluidand gradient flow. In certain aspects, the invention concerns a newapproach to wound healing, flow (or gradient) activated tissueengineering. In rudimentary form, this approach involves a source orgenerator of flow that forms a gradient for controlled movement ofeither endogenous or exogenous fluids into, out of, or through a tissuespace for the organized deposition of proteins and/or spatialconcentration of cytokines and growth factors, with subsequent formationof a directionally oriented provisional matrix. The tissue space beingdefined here includes, but is not limited to, the region surrounding asite of nerve tissue damage.

Fluid flow into, through, or out of the nerve tissue space can berefined and directed through the inclusion of additional elements to thesystem including manifolds and/or scaffolds. The coordinated elements ofthe system are designed to create flow parameters, pathways, andpatterns sufficiently detailed in scale as to be able to influence anddirect the controlled adsorption of proteins, the organization ofmatrix, and organized colonization of specific cell types. Individualelements of the system are as follows.

Source or generator of flow. Flow is induced into, through, or out ofthe nerve tissue space by methods or apparatuses that introduce changesin mechanical, chemical, and/or electrical potentials. These generatorsof flow provide either a gradient or a change in potential from the siteor reservoir of endogenous or exogenous fluids to the placement positionof the flow generator or its extension element (i.e., manifold orscaffold). In one embodiment, the source of flow comprises a source ofreduced pressure. Systems and apparatuses according to the invention mayalso comprise valves or arrays of valves that control the applicationand amount of negative pressure applied to the manifold. In certainaspects, nerve conduits and/or manifolds described herein comprise apressure sensor. Thus, in some embodiments, the amount of negativepressure applied by a source is regulated based on the amount ofnegative pressure that is sensed in the manifold or nerve conduit or atthe site of tissue damage.

Manifold. The flow generators are the driving force for stimulating theflow of fluids. Manifolds are apparatuses for refining the pattern offlow between the source or generator of flow and the tissue space. Themacroscale level of flow is refined by specialized manifolds utilizedfor directed localization to a single point or to a plurality ofselectively positioned points for creating initiation sites formicroscale flow pathways within the manifold/scaffold and, ultimately,the tissue space. The manifold may also serve as a conduit for theremoval of fluids from and as an apparatus for the delivery of exogenousfluids to the tissue space.

A manifold generally refers to a physical substance or structure thatserves to assist in applying and translating a mechanical, chemical,electrical or similar alterations into changes in the flow of a fluid,herein defined as the movement of liquids, gases, and other deformablesubstances such as proteins, cells, and other like moieties. As such,this physical device includes a single point or plurality of points forthe egress or evacuation of pressure, fluids, and like substancescapable of translating the movement of fluids in a scaffold, as definedabove. This can include, but is not limited to, the introduction ofexogenous factors such as cells and/or therapeutic moieties into thescaffold through the lumen or plurality of lumens present in themanifold. In addition, as used herein, a manifold includes a singlepoint or plurality of points for the ingress or introduction of fluidfrom the scaffold back towards the point source of flow.

Flow distributed by the manifold can direct the movement of endogenousproteins, growth factors, cytokines, and cells from their residentlocations within the host to the tissue space or scaffold in anorganized manner. The establishment of flow along these pathways leadsto the deposition of proteins and provisional matrix that creates aninterfacial endogenous network connecting the host to the scaffold.Extensions of this matrix can be established within the scaffold throughselective positioning of the manifold flow initiation sites with flowpromoting scaffolding designs. The organized protein deposition andprovisional matrix provide a biochemical and physical framework thatstimulates the attachment and migration of cells along directed pathwaysthroughout the scaffold and the tissue space. The resulting endogenousnetwork of proteins, growth factors, and cells provides a foundationupon which subsequent phases of the body's own tissue repair andregeneration mechanisms can build.

When in place, the manifold works in conjunction with a flow generatingsource and a scaffold, if present. Flow generating sources include, butare not limited to generators of negative pressure; generators ofpositive pressure; and generators of osmotic flow. The flow gradientestablished in the manifold may be further refined through the scaffold,to deliver a flow gradient to the scaffold to optimize flow through thescaffold as needed for the particular defect. Many of the embodimentsdisclosed herein are manifolds capable of translating changes inpressure and the like into controlled movement of fluids, optionallythrough a physical scaffold, for the purposes of directed tissueregeneration. These embodiments are generally specified for a particularapplication in the regeneration of specific tissues, but are not limitedto a particular tissue therein.

In order to realize the goal of inducing flow for the purpose of tissueregeneration, alterations in the aforementioned mechanical, chemical, orelectrical impetus must be translated from the singular gradient sourcetoward a physical substrate or scaffold to elicit cellular-level changesin protein adsorption, matrix organization, cell migration, and othertissue regeneration-related behaviors. These alterations aremultivariate in nature and can include mechanical changes that elicit aphysical change in pressure applied to the scaffold as applied to thesite of the wound or desired site of tissue regeneration, chemicalchanges that elicit a gradient in protein and/or ion concentrations,which result in the creation of osmotic gradients capable of inducingflow, or electrical changes that create a gradient of current/ionexchange allowing for propagation of electrical signals from the pointsource. It is to be understood, however, that the applicants are notbound by any particular mechanism through which gradients and fluid flowinduce advantageous results in tissue repair or growth. In order toadvantageously transmit these gradients to the tissue, a physical deviceis needed to direct the path of flow from its source to the scaffold ortissue site and vice versa.

In some embodiments, the manifold comprises a physical structure inclose apposition to or within the contents of a scaffold and serves topropagate an alteration in a physical parameter, whether it bemechanical, chemical, electrical, or something similar in nature, forthe means of directing these changes from its point source to thescaffolding material. The placement of this manifold with respect to itslocation with regard to that of the scaffold may be of crucialimportance for facilitating controlled and directed regeneration ofspecific tissue types. For example, in peripheral nerve whereregeneration primarily occurs in a unidirectional manner from theproximal to distal nerve stumps, it may be important to place themanifold along the length of a nerve conduit more towards it distal endto help direct regeneration towards that end. However, it may also beimportant to not place the manifold at the most distal aspect of thescaffold/conduit as soluble factors derived from the distal stump havebeen shown to be important for directing nerve regeneration towards itssource.

Manifolds may be composed of a bioabsorbable or bioinert material.Examples include non-bioabsorbable materials such as medical gradesilicone polymers, metals, polyvinylchloride (PVC), and polyurethane.Bioabsorbable polymers such as collagen, polylactic acid (PLA),polyglycolic acid (PGA), polylactide-co-glycolide (PLGA), apolysaccharide, a hydroxyapatite, or a polyethylene glycol, orcombinations thereof, can also be used. Some manifolds are also a mix ofnon-bioresorbable and bioresorbable materials. In general material usedfor a scaffold may also be used to compose a manifold and such materialsare further detailed below. In certain aspects, manifold materials arestructured to include a high void fraction for improved bioabsorptionproperties.

Support. Manifold support structures may be composed of any acceptablebiocompatible material. A support structure will typically beimpermeable and surround the manifold so as to maintain manifoldpressure.

A portion of the support, such as a flange, couples the manifold and thenerve conduit. In certain aspects, a flange is attached to the exteriorsurface of a nerve conduit with an adhesive such as a fibrin glue,cyanoacrylate, or other biologically derived adhesive. A support mayalso be connected to a nerve conduit via reversible mechanisms otherthan an adhesive, such as chemical, thermal, osmotic, mechanical (snapor other interference fit, threaded, etc), magnetic, and electrostaticmechanisms. The manifold may be used to deliver agents that reverse theaction of the binding mechanism in order to detach the support from thenerve conduit (e.g., upon completion of therapy). For example,electrostatic binding may be released through introduction of saltsolutions or biocompatible solvents may be used to release adhesives.

Scaffold. Biologic and synthetic scaffolds are used in the field oftissue engineering to support protein adhesion and cellular ingrowth fortissue repair and regeneration. The current state of the art in scaffoldtechnology relies upon the inherent characteristics of the surroundingtissue space for the adsorption of proteins and migration of cells. Ascaffold for use according to the invention is coupled to a manifold,provides physical guidance to direct the pathway of fluid flow in thetissue site, creating avenues for the movement and migration of adhesiveproteins and cells, respectively, which are in tern integral to theestablishment of a provisional matrix in predetermined patterns oforganization within the tissue space. The methods and apparatusesdescribed for fluid flow-induced and gradient-induced generation oftissues have direct implications in the design of the scaffolds. Withinthis context, scaffolds serve to refine the pathways of fluid flowwithin the tissue space to cellular level patterns from the fluid sourceto the point(s) of flow initiation within the manifold. A scaffold mayembody characteristics of a manifold or be combined in conjunction witha manifold for refinement of the flow pathways within the tissue site.In certain aspects, a scaffold is a reticulated structure comprisinghigh void fraction for improved bioabsorption properties.

Nonlimiting examples of suitable scaffold materials includeextracellular matrix proteins such as fibrin, collagen or fibronectin,and synthetic or naturally occurring polymers, including bioabsorbableor non-absorbable polymers, such as polylactic acid (PLA), polyglycolicacid (PGA), polylactide-co-glycolide (PLGA), polyvinylpyrrolidone,polycaprolactone, polycarbonates, polyfumarates, caprolactones,polyamides, polysaccharides (including alginates (e.g., calciumalginate) and chitosan), hyaluronic acid, polyhydroxybutyrate,polyhydroxyvalerate, polydioxanone, polyorthoesthers, polyethyleneglycols, poloxamers, polyphosphazenes, polyanhydrides, polyamino acids,polyacetals, polycyanoacrylates, polyurethanes, polyacrylates,ethylene-vinyl acetate polymers and other acyl substituted celluloseacetates and derivatives thereof, polystyrenes, polyvinyl chloride,polyvinyl fluoride, poly(vinylimidazole), chlorosulphonated polyolefins,polyethylene oxide, polyvinyl alcohol, Teflon®, and nylon. The scaffoldcan also comprise ceramics such as hydroxyapatite, coralline apatite,calcium phosphate, calcium sulfate, calcium carbonate or othercarbonates, bioglass, allografts, autografts, xenografts, decellularizedtissues, or composites of any of the above. In particular embodiments,the scaffold comprises collagen, polylactic acid (PLA), polyglycolicacid (PGA), polylactide-co-glycolide (PLGA), a polyurethane, apolysaccharide, an hydroxyapatite, or a polytherylene glycol.Additionally, the scaffold can comprise combinations of any two, threeor more materials, either in separate or multiple areas of the scaffold,combined noncovalently, or covalently (e.g., copolymers such as apolyethylene oxide-polypropylene glycol block copolymers, orterpolymers), or combinations thereof. Suitable matrix materials arediscussed in, for example, Ma and Elisseeff, 2005, and Saltzman, 2004.

Bioactive Agents

In certain aspects, the apparatuses and methods according to theinvention concern bioactive agents. Bioactive agents may, in some cases,be incorporated directly onto a manifold or scaffold material (i.e., togenerate a bioactive manifold and/or scaffold). For example, agents thatfacilitate tissue growth such as collagen or fibrin may be directlyincorporated onto or into a manifold or scaffold material. Likewise, inapplications where aberrant immune response need be avoided (e.g.,tissue grafts) immune regulator agents such as rapamycin may beincorporated into manifold or scaffold structures.

In further aspects, soluble bioactive agents may be introduced at a siteof tissue damage by virtue of the flow through the tissue site. Forexample, a manifold may be in fluid communication with a fluid sourceand a bioactive agent may be introduced into the fluid source andthereby into the manifold and damaged nerve tissue.

Nonlimiting examples of bioactive growth factors for variousapplications are growth hormone (GH), a bone morphogenetic protein(BMP), transforming growth factor-α (TGF-α), a TGF-β, a fibroblastgrowth factor (FGF), granulocyte-colony stimulating factor (G-CSF),granulocyte/macrophage-colony stimulating factor (GM-CSF), epidermalgrowth factor (EGF), platelet derived growth factor (PDGF), insulin-likegrowth factor (IGF), vascular endothelial growth factor (VEGF),hepatocyte growth factor/scatter factor (HGF/SF), an interleukin, tumornecrosis factor-α (TNF-α) or nerve growth factor (NGF).

Nerve tissue repair and engineering. The apparatuses and systemsdisclosed herein can be used for nerve tissue repair and engineering invarious contexts including the following.

Repair and regeneration of lost tissue. A generator of flow may becombined with manifolds and/or scaffolds to direct the regeneration oflost tissue at a site of injury or compromised function. Tissues lostfrom traumatic injury, surgery, burns, or other causes (e.g., infectionor autoimmune disease) can be led to regenerate using the methods,scaffolds, manifolds, flow sources and systems of the invention.Functional nerve tissue is directed to regenerate.

Retard the progression of a tissue disease state. A generator of flowmay be combined with manifolds and/or scaffolds to retard diseaseprogression of an affected nerve tissue such as occurs, e.g., inautoimmune disease.

Maintenance of tissue viability. A generator of flow may be combinedwith manifolds and/or scaffolds to maintain the viability of explantedtissues either for in vitro study, ex vivo scaffold or implantpreparation, or in vivo transplant. A generator of flow combined with amanifold may be used to provide nutrient flow to the tissue and tocontrol waste removal from the tissue.

Expansion of tissue. A generator of flow may be combined with manifoldsand/or scaffolds to promote the expansion of existing tissues. Themethods, scaffolds, manifolds, flow sources and systems of the inventioncan be used to direct the growth of tissues where additional tissuequantity is needed or desired.

Acceleration of tissue formation. A generator of flow may be combinedwith manifolds and/or scaffolds to accelerate the rate of tissueformation within a natural healing response. The methods, scaffolds,manifolds, flow sources, and systems of the invention may be used toaccelerate tissue growth by augmenting formation of provisionalmatrices, facilitating its stable positioning, and aiding in recruitmentof cells to the tissue space.

Stimulating the differentiation of stem cells along specific pathways. Agenerator of flow may be combined with manifolds and/or scaffolds tostimulate the differentiation of stem cells or other pluripotent cellsinto specific lineages. Application of flow using the methods,scaffolds, manifolds, flow sources and systems of the invention may beused to direct pluripotent cells into specific cell lineages needed tofoster growth in the tissue space.

Introducing proteins, matrix, cells, or pharmaceuticals into the in vivoenvironment. A generator of flow may be combined with manifolds and/orscaffolds to introduce exogenous growth factors, proteins, cells, orpharmaceutical agents into the tissue space to augment tissue repair,regeneration, and/or maintenance.

Creating matrices in vitro for implantation in vivo. A generator of flowmay be combined with manifolds and/or scaffolds to facilitate formationof matrices in vitro that may subsequently be used for in vivotransplantation.

Promoting integration of transplanted tissue. A generator of flow may becombined with manifolds and/or scaffolds to promote integration oftransplanted tissue into the host environment. This can be applied toautograft, allograft, or xenograft transplants.

Directing extracellular matrix (ECM) deposition and orientation invitro. A flow generator may be combined with manifolds and/or scaffoldsto guide the directed deposition and orientation of ECM expressed bycells and tissues. The directed orientation of ECM has an impact inorganizing and directing the attachment and colonization of subsequentcell layers and tissues.

REFERENCES

-   U.S. Pat. No. 4,787,906-   U.S. Pat. No. 6,103,255-   U.S. Pat. No. 6,135,116-   U.S. Pat. No. 6,365,146-   U.S. Pat. No. 6,695,823-   U.S. Pat. No. 6,696,575-   U.S. Pat. No. 6,767,334-   U.S. Pat. No. 6,814,079-   U.S. Pat. No. 6,856,821-   U.S. Pat. No. 6,936,037-   U.S. Pat. No. 6,951,553-   U.S. Pat. No. 6,994,702-   U.S. Pat. No. 7,004,915-   U.S. Pat. No. 7,070,584-   U.S. Pat. No. 7,077,832-   U.S. Pat. No. 7,108,683-   U.S. Pat. No. 7,160,553-   U.S. Pat. No. 7,186,244-   U.S. Pat. No. 7,214,202-   U.S. Pat. No. 7,279,612-   U.S. Pat. No. 7,316,672-   U.S. Pat. No. 7,346,945-   U.S. Pat. No. 7,351,250-   U.S. Pat. No. 7,384,786-   U.S. Patent Pubin. 2003/0225347-   U.S. Patent Pubin. 2005/0260189-   U.S. Patent Publn. 2007/0123895-   U.S. Patent Pubin. 2008/0033324-   U.S. Patent Pubin. 2008/0208358-   U.S. Provisional Patent Appln. 61/142,053-   U.S. Provisional Patent Appln. 61/142,065-   Anderson et al., Tissue Eng., 13:2525-38, 2007.-   Brody et al., J. Biomed. Mater. Res. B: Appl. Biomater., 83:16-43,    2007.-   Gemmiti et al., Tissue Eng., 12:469-79, 2006.-   Lago et al., IEEE Trans. Biomed. Eng., 54:1129-37, 2007.-   Ma et al., Scaffolding in Tissue Engineering, 2005.-   Manwaring et al., Biomaterials, 22:3155-3168, 2001.-   Manwaring et al., Biomaterials, 25:3631-3638, 2004.-   Mercier et al., Biomaterials, 26:1945-1952, 2005.-   Mikos et al., J. Biomed. Mater. Ref, 27:183-189, 2004.-   Norman et al., Ann Biomed Eng., 34:89-101, 2006.-   PCT Appln. WO 00/38755A2-   PCT Appln. WO 00/61206A1-   PCT Appln. WO 03/018098A2-   PCT Appln. WO 03/092620A2-   PCT Appln. WO 04/060148A2-   PCT Appln. WO 04/105576A2-   PCT Appln. WO 05/009488A2-   PCT Appln. WO 05/033273A2-   PCT Appln. WO 06/004951-   PCT Appln. WO 06/127853-   PCT Appln. WO 07/067,685A2-   PCT Appln. WO 07/092,397A2-   PCT Appln. WO 07/106,589A2-   PCT Appln. WO 07/106,590A2-   PCT Appln. WO 07/106,591A2-   PCT Appln. WO 07/106,592A2-   PCT Appln. WO 07/106,594A2-   PCT Appln. WO 07/133,555A2-   PCT Appln. WO 07/133,556A2-   PCT Appln. WO 07/143,060A2-   PCT Appln. WO 07/196,590-   PCT Appln. WO 08/013,896A2-   PCT Appln. WO 08/036,162A2-   PCT Appln. WO 08/036,359A2-   PCT Appln. WO 08/036,361A2-   PCT Appln. WO 08/042,481A2-   PCT Appln. WO 08/091,521A2-   Pfister et al., Neurosurgery, 60:137-41, 2007.-   Saltzman, Tissue Engineering: Engineering Principles for the Design    of Replacement Organs and Tissues, 2004.-   Sachlos et al., Cells and Mat., 5:29-40, 2003.-   Segvich et al., J. Biomed. Mater. Res. B: Appl. Biomater.,    84B:340-349, 2008.-   Shimko et al., J Biomed Mater. Res. B: Appl. Biomater., 73:315-24,    2005.-   Takahashi et al., Cell, 126:663-76, 2006.-   Tan et al., Bone, 41:745-751, 2007.-   Tan et al., Biochem. Biophys. Res. Comm., 369:1150-1154, 2008.-   Walsh et al., Tissue Eng., 11:1085-1094, 2005.-   Wen et al., Handbook of Nanostructured Biomaterials and Their    Applications in Nanobiotechnology, 1-23, 2005.

All references cited in this specification are hereby incorporated byreference. The discussion of the references herein is intended merely tosummarize the assertions made by the authors and no admission is madethat any reference constitutes prior art. Applicants reserve the rightto challenge the accuracy and pertinence of the cited references.

In view of the above, it will be seen that the advantages of theinvention are achieved and other advantages attained. As various changescould be made in the above methods and compositions without departingfrom the scope of the invention, it is intended that all mattercontained in the above description and shown in the accompanyingdrawings shall be interpreted as illustrative and not in a limitingsense.

1. An apparatus for providing reduced pressure from a reduced-pressuresource to a defect at a tissue site of a nerve, the apparatuscomprising: a nerve conduit having a generally tubular shape havingwalls including an exterior wall and a luminal wall surrounding thetissue site to contain fluids within a luminal space between the tissuesite and the luminal wall; a manifold having a generally cylindricalbody having surfaces including a side wall surface and two end wallsurfaces, a first end wall surface of the two end wall surfaces forreceiving reduced pressure, a fluid contact surface including a firstportion of the surfaces of the cylindrical body other than the first endwall surface for fluid communication with the luminal space, and asupport surface including a second portion of the surface of thecylindrical body other than the first end wall surface and the fluidcontact surface; and a first support structure having a generallytubular shape for enclosing the support surface, a first end portion forcoupling the first end wall surface to the reduced-pressure source, anda second end portion for coupling the manifold to the nerve conduit in agenerally radial direction with respect to the luminal wall.
 2. Theapparatus of claim 1, wherein the fluid contact surface comprises asecond end wall surface of the two end wall surfaces positioned adjacentthe luminal wall to fluidly communicate with the luminal space.
 3. Theapparatus of claim 2, wherein the nerve conduit comprises a materialgenerally impermeable to fluids from tissue surrounding the nerveconduit.
 4. The apparatus of claim 1, wherein the nerve conduit isporous and the fluid contact surface comprises a second end wall surfaceof the two end wall surfaces positioned adjacent the exterior surface ofthe nerve conduit to fluidly communicate with the luminal space throughthe walls of the nerve conduit.
 5. The apparatus of claim 4, wherein thenerve conduit comprises a material generally impermeable to fluids fromtissue surrounding the nerve conduit.
 6. The apparatus of claim 1,wherein the fluid contact surface comprises a second end wall surface ofthe two end wall surfaces and a portion of the side wall surfaceadjacent the second end wall surface extending from the luminal wallinto the luminal space.
 7. The apparatus of claim 1, wherein the fluidcontact surface comprises a portion of the side wall surface extendingfrom a first side of the luminal wall through the luminal space to asecond side of the luminal wall, and a second end wall surface of thetwo end wall surfaces for receiving a fluid from a fluid source, theapparatus further comprising: a second support structure having agenerally tubular shape for enclosing the support surface adjacent thesecond end wall surface, a first end portion for coupling the second endwall surface to the fluid source, and a second end portion for couplingthe manifold to the nerve conduit.
 8. The apparatus of claim 1, whereinthe defect is a severed, partially severed, pinched, or degeneratednerve.
 9. The apparatus of claim 1, wherein the second end portion ofthe support structure comprises a flange.
 10. The apparatus of claim 1,wherein the second end portion of the support structure provides adetachable coupling of the manifold to the nerve conduit.
 11. Theapparatus of claim 1, wherein the second end portion of the supportstructure comprises an adhesive for coupling the manifold and the nerveconduit.
 12. The apparatus of claim 1, wherein the manifold comprises aporous structure wherein the pore size is sufficiently small to excludecells from entering the manifold.
 13. The apparatus of claim 1, whereinthe manifold serves as a scaffold that facilitates tissue growth orregrowth.
 14. The apparatus of claim 1, wherein the nerve conduitcomprises pores that are sufficiently small to exclude the entry ofcells into the luminal space.
 15. The apparatus of claim 14, wherein thepores have an interior diameter of between about 5 μm and 50 μm.
 16. Theapparatus of claim 1, wherein the manifold is positioned on the distalside of the nerve conduit relative to the tissue site.
 17. The apparatusof claim 1, wherein the manifold provides reduced pressurepreferentially to the distal side of the nerve relative to the tissuesite.
 18. The apparatus of claim 1, wherein the manifold or nerveconduit is composed of a bioinert material.
 19. The apparatus of claim1, wherein the manifold or nerve conduit is composed of a bioabsorbablematerial.
 20. The apparatus of claim 1, wherein the luminal space of thenerve conduit comprises a scaffold that facilitates tissue growth orregrowth.
 21. The apparatus of claim 20, wherein the scaffold is formedfrom a foam or gel material.
 22. The apparatus of claim 20, wherein thescaffold is biological material selected from fibrin or collagen. 23.The apparatus of claim 22, wherein the scaffold material comprises abioactive agent.
 24. The apparatus of claim 23, wherein the bioactiveagent is at least one of an antibiotic, an antibody and a growth factor.25. The apparatus of claim 24, wherein the bioactive agent is a growthhormone (GH), a bone morphogenetic protein (BMP), transforming growthfactor-α (TGF-α), a TGF-β, a fibroblast growth factor (FGF),granulocyte-colony stimulating factor (G-CSF),granulocyte/macrophage-colony stimulating factor (GM-CSF), epidermalgrowth factor (EGF), platelet derived growth factor (PDGF), insulin-likegrowth factor (IGF), vascular endothelial growth factor (VEGF),hepatocyte growth factor/scatter factor (HGF/SF), an interleukin, tumornecrosis factor-α (TNF-α) or nerve growth factor (NGF).
 26. Theapparatus of claim 1, wherein the nerve conduit comprises a slice alongits length that forms an opening whereby the nerve conduit isimplantable around the tissue site and sealable with one or more closureelements.
 27. A system for providing reduced pressure to a defect at atissue site of a nerve, the system comprising: a pressure source forsupplying the reduced pressure; a nerve conduit having a generallytubular shape having walls including an exterior wall and a luminal wallsurrounding the tissue site to contain fluids within a luminal spacebetween the tissue site and the luminal wall; a manifold having agenerally cylindrical body having surfaces including a side wall surfaceand two end wall surfaces, a first end wall surface of the two end wallsurfaces in fluid communication with the pressure source, a fluidcontact surface including a first portion of the surfaces of thecylindrical body other than the first end wall surface for fluidcommunication with the luminal space, and a support surface including asecond portion of the surface of the cylindrical body other than thefirst end wall surface and the fluid contact surface; and a firstsupport structure having a generally tubular shape for enclosing thesupport surface, a first end portion for coupling the first end wallsurface to the reduced-pressure source, and a second end portion forcoupling the manifold to the nerve conduit in a generally radialdirection with respect to the luminal wall. 28.-53. (canceled)
 54. Amethod for providing reduced pressure to a defect at a tissue site of anerve, the method comprising: implanting a nerve conduit having agenerally tubular shape having walls including an exterior wall and aluminal wall; sealing the nerve conduit around the tissue site tocontain fluids within the luminal space between the tissue site and theluminal wall; implanting a manifold and a support structure at thetissue site wherein the manifold has a generally cylindrical body havingsurfaces including a side wall surface and two end wall surfaces, afirst end wall surface of the two end wall surfaces for receivingreduced pressure, a fluid contact surface including a first portion ofthe surfaces of the cylindrical body other than the first end wallsurface for fluid communication with the luminal space, and a supportsurface including a second portion of the surface of the cylindricalbody other than the first end wall surface and the fluid contact surfaceand wherein the support structure has a generally tubular shape forenclosing the support surface, a first end portion for coupling thefirst end wall surface to the reduced-pressure source, and a second endportion for coupling the manifold to the nerve conduit in a generallyradial direction with respect to the luminal wall; and applying reducedpressure through the manifold to the tissue site. 55.-56. (canceled)